Assessing the Effects of Teriparatide Treatment on Bone Mineral Density, Bone Microarchitecture, and Bone Strength.

BACKGROUND: To gain insight into how teriparatide affects various bone health parameters, we assessed the effects of teriparatide treatment with use of standard DXA (dual x-ray absorptiometry) technology and two newer technologies, high-resolution MRI (magnetic resonance imaging) and finite element analysis of quantitative CT (computed tomography) scans. METHODS: In this phase-4, open-label study, postmenopausal women with severe osteoporosis received 20 µg/day of teriparatide. Assessments included (1) changes in areal BMD (bone mineral density) (in g/cm2) at the radius, spine, and hip on DXA, (2) changes in volumetric BMD (in mg/cm3) at the spine and hip on quantitative CT scans, (3) changes in bone microarchitecture at the radius on high-resolution MRI, (4) estimated changes in spine and hip strength according to finite element analysis of quantitative CT scans, (5) changes in bone turnover markers in serum, and (6) safety. RESULTS: Thirty-five subjects were enrolled; thirty completed eighteen months and twenty-five completed an optional six-month extension. No significant changes were observed for the primary outcome, high-resolution MRI at the distal aspect of the radius. At month eighteen, the least-squares mean percentage change from baseline in total volumetric BMD at the spine was 10.05% (95% confidence interval [CI], 6.83% to 13.26%; p < 0.001), and estimated spine strength increased 17.43% (95% CI, 12.09% to 22.76%; p < 0.001). Total volumetric BMD at the hip increased 2.22% (95% CI, 0.37% to 4.06%; p = 0.021), and estimated hip strength increased 2.54% (95% CI, 0.06% to 5.01%; p = 0.045). Areal BMD increased at the lumbar spine and femoral neck, was unchanged for the total hip and at the distalmost aspect of the radius, and decreased at a point one-third of the distance between the wrist and elbow. Bone turnover markers increased at months three, six, and twenty-four (all p < 0.05). No unexpected adverse events were observed. CONCLUSIONS: High-resolution MRI failed to identify changes in bone microarchitecture at the distal aspect of the radius, a non-weight-bearing site that may not be suitable for assessing effects of an osteoanabolic agent. Teriparatide increased areal BMD at the spine and femoral neck and volumetric BMD at the spine and hip. Estimated vertebral and femoral strength also increased. These findings and increases in bone turnover markers through month twenty-four are consistent with the known osteoanabolic effect of teriparatide. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Use of DXA-based technology for detection and assessment of risk of vertebral fracture in rheumatology practice.

Measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) is the recommended method for diagnosis of osteoporosis and assessment of future fracture risk. However, most patients who will suffer fractures do not have osteoporosis by DXA (T-score of -2.5 or less). Bone strength, which is most closely associated with resistance to fracture, is a composite of both bone density and bone quality, and the latter is not measured by DXA. Thus, other technology is needed for non-invasive and inexpensive assessment of bone strength and fracture risk. Vertebral fractures, the most common clinical fracture in the general population, are of even greater importance in rheumatoid arthritis and other rheumatic disorders. Vertebral fracture assessment (VFA) and trabecular bone scores (TBS), two techniques which can aid prediction of future fracture risk, can be used with currently available DXA machines. Description of these techniques and their potential application to clinical rheumatology practice will be the focus of this paper.

Twice daily versus once nightly dosing of pregabalin for fibromyalgia: a double-blind randomized clinical trial of efficacy and safety.

OBJECTIVE: To compare the efficacy, discontinuation rates, and safety of once nightly versus twice daily dosing of pregabalin in a community-based trial. METHODS: This multicenter, double-blind, 8-week randomized clinical trial compared the effects of 300-mg daily doses of pregabalin given either twice daily or once nightly for the treatment of fibromyalgia in 177 patients. The primary outcome was the comparison of end point mean pain scores derived from a daily diary. RESULTS: Both twice daily (88 patients randomized) and once nightly (89 patients) pregabalin significantly reduced the average severity of pain experienced by patients (P < 0.001 for both). Treatment-emergent adverse events were reported by significantly more patients in the twice daily group than those in the once nightly group (P = 0.023). There were no significant differences between the groups for the frequencies of individual adverse events (P > 0.05 for all). There was no significant difference in adverse events or efficacy in patients taking both pregabalin and a selective serotonin and norepinephrine reuptake inhibitor or selective serotonin uptake inhibitor. CONCLUSION: While a nightly dosing schedule of pregabalin has been used by clinicians hoping to improve treatment, this study showed no significant difference (either beneficial or detrimental) between either treatment option. While there was a decrease in total patient-reported adverse events in the once nightly arm, the lack of specificity in relation to a particular adverse event suggested no real difference in adverse events.

Oral calcitonin.

Both injectable and nasal spray calcitonins have been utilized in the treatment of postmenopausal osteoporosis for over 25 years. More widespread use of calcitonin in the treatment of osteoporosis has been hampered in part due to poor patient acceptability and compliance and the inability of patients to take this medication as an oral pill. In recent years, an oral preparation of calcitonin has been developed that combines the active peptide hormone with a caprylic acid derivative to enhance bioavailability. Clinical trials with oral calcitonin in patients with osteoarthritis are currently being conducted. A recent phase 3 study failed to demonstrate significant vertebral fracture reduction, and as a result the clinical program for oral calcitonin in osteoporosis is under review for further consideration.

Update on glucocorticoid-induced osteoporosis.

Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, and fractures are the most frequent adverse effects of this medication. Glucocorticoids have several direct and indirect adverse effects on bone, primarily through reduction in osteoblasts and osteocyte activity, and life span. Recent advances in the pathophysiology and prevention of this complication of therapy provide hope for its amelioration in patients being treated with glucocorticoids. Several effective pharmacologic agents are now available, and guidelines for the prevention and treatment of GIOP have been published. Despite these advances, many patients still do not receive proper prevention or therapy.

Osteoporosis update from the 2010 santa fe bone symposium.

The 11th Santa Fe Bone Symposium was held in Santa Fe, NM, USA, on August 6-7, 2010. This annual event addresses clinically relevant advances in the fields of osteoporosis and metabolic bone disease. The venue includes plenary presentations by internationally recognized experts, oral presentations of abstracts, and interactive panel discussions of challenging cases and controversial issues. Attendees are active participants throughout the symposium program. Topics for the 2010 symposium included potential applications of novel technologies for the assessment of skeletal health for research and clinical practice; new and emerging treatments for osteoporosis; appropriate use of pharmacological agents to prevent osteoporosis; controversies with bisphosphonate therapy; practical applications of the World Health Organization fracture risk assessment tool (FRAX; World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK); insights into the use of osteoanabolic agents to enhance fracture healing; and challenges in laboratory testing in the assessment of factors contributing to skeletal fragility. Concurrent sessions focused on critical thinking for technologists in the acquisition and analysis of data with dual-energy X-ray absorptiometry. The key messages from each presentation, including the best available medical evidence and potential current and future clinical applications, are provided here.

The role of zoledronic acid in the management of osteoporosis.

Bisphosphonates are the current standard of care for treatment of osteoporosis. However, oral bisphosphonates are associated with complicated dosing regimens because of poor absorption and have the potential for upper gastrointestinal (GI) tract irritation, resulting in poor adherence and persistence. Zoledronic acid (ZOL) 5 mg, a once-yearly intravenous bisphosphonate, is approved for treatment and prevention of postmenopausal osteoporosis, increasing bone mass in men with osteoporosis, and treatment and prevention of glucocorticoid-induced osteoporosis. Because it is administered as an infusion, ZOL ensures adherence and persistence over the entire 12-month dosing interval and bypasses the GI absorption/irritation problems associated with oral bisphosphonates. The objective of this study was to review the safety and efficacy of 5 mg ZOL and its potential for improving patient compliance. Published reports dating back to 2001 were reviewed, with emphasis on osteoporosis treatment. In the HORIZON-Pivotal Fracture Trial, annual infusions of 5 mg ZOL produced significant reductions in risk of morphometric vertebral fractures (70%) and hip fractures (41%) vs placebo over 3 years in postmenopausal women with osteoporosis. In the HORIZON-Recurrent Fracture Trial, an annual infusion of 5 mg ZOL after repair of a recent low-trauma hip fracture was associated with significant reductions in risk for new clinical fractures (35%) vs placebo. In men with osteoporosis, an annual treatment of ZOL over 2 years increased lumbar spine bone mineral density (BMD) by 6% compared with baseline. In patients starting or continuing treatment with chronic glucocorticoids, ZOL resulted in significantly greater increases in lumbar spine BMD over 1 year than an oral bisphosphonate. In postmenopausal women with osteopenia, a single infusion of ZOL over a 2-year period produced significantly greater gains in lumbar spine and hip BMD than placebo. ZOL is generally safe and well tolerated. Five milligrams of ZOL has the potential to improve compliance with osteoporosis therapy and, consequently, to reduce fracture risk in clinical practice.

Intravenous zoledronic acid: what are the indications for male osteoporosis?

Osteoporosis and fractures are under-recognized and undertreated, both in men and women worldwide. Male osteoporosis is not the epidemic problem that female osteoporosis is; however, the National Osteoporosis Foundation estimates that over 14 million American men have osteoporosis or low bone mass, and approximately 25% to 30% of all hip fractures occur in male individuals who incur greater morbidity and mortality than their female counterparts. Until recently, alendronate, risedronate, and teriparatide were the only pharmacologic agents approved by the US Food and Drug Administration for treating male osteoporosis. In December 2008, zoledronic acid was approved for "treatment to increase bone mass in men with osteoporosis." In 2009, zoledronic acid was also approved for "treatment and prevention of glucocorticoid-induced osteoporosis in patients (both men and women) expected to be on glucocorticoids for at least 12 months."

Safety, tolerability, and clinical outcomes after intraarticular injection of a recombinant adeno-associated vector containing a tumor necrosis factor antagonist gene: results of a phase 1/2 Study.

OBJECTIVE: To assess safety and clinical outcomes in patients with inflammatory arthritis after intraarticular (IA) injection of rAAV2-TNFR:Fc, a recombinant adeno-associated viral vector containing the human tumor necrosis factor (TNF) receptor-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) gene. METHODS: In this phase 1/2 randomized study, adults with persistent moderate or severe inflammation in a target joint, being treated with or without systemic anti-TNF therapy, received a single IA injection of either rAAV2-TNFR:Fc (1 x 10(11), 1 x 10(12), or 1 x 10(13) DNase-resistant particles/ml joint volume) or placebo, followed by open-label rAAV2-TNFR:Fc 12-30 weeks later, depending on when the target joint met predetermined criteria for reinjection. RESULTS: 127 subjects received the first injection of blinded study drug; 95 subjects received open-label rAAV2-TNFR:Fc. Administration site reactions, consisting of transient mild to moderate increases in tenderness and swelling of the injected joint, occurred after 23/191 (12%) rAAV2-TNFR:Fc injections and were dose-dependent. Rates of other adverse events were not dose-dependent. Notable serious adverse events (SAE) included culture-negative septic arthritis in a subject receiving leflunomide and fatal disseminated histoplasmosis considered unrelated to rAAV2-TNFR:Fc in a subject receiving adalimumab. In the phase 2 portion of the study, a 30% decrease in target joint global visual analog scale was observed in 21/50 (42%) rAAV2-TNFR:Fc subjects and 3/16 (19%) placebo subjects 12 weeks after first injection (p = 0.14). CONCLUSION: IA rAAV2-TNFR:Fc resulted in administration site reactions after 12% of injections. A fatal SAE, disseminated histoplasmosis, was considered not related to study agent. Patient-reported outcome measures of clinical response showed greater improvement in treated patients than placebo patients.

Osteomalacia.

The finding of low bone mineral density with a T-score of -2.5 or below on dual energy x-ray absorptiometry is usually reported as indicating that the patient has "osteoporosis" according to the World Health Organization classification, and, in postmenopausal women, it is often assumed that this is due to estrogen deficiency. However, up to one third of postmenopausal women have a secondary cause of low density, including osteomalacia. Osteomalacia is defined as a mineralization defect caused by disorders that lead to decreased mineralization of bone. Clues from the history, physical examination, laboratory tests, and radiographs may indicate that the patient suffers from a form of osteomalacia rather than postmenopausal estrogen deficiency alone. Establishing a diagnosis of osteomalacia when present is critical to proper management of the patient.

Dual-Energy X-Ray Absorptiometry Technical issues: the 2007 ISCD Official Positions.

At the 2007 Position Development Conference, the Dual-Energy X-ray Absorptiometry Technical Task Force investigated three major areas of bone density testing. Although bone mineral density (BMD) testing in men had previously been reviewed at the 2005 Position Development Conference, we reviewed the most recent data in men to develop appropriate indications for bone density testing in men. We continue to recommend screening at age 70 and discuss the clinical risk factors that may be an appropriate indication for earlier BMD testing. Menopausal transition (perimenopause) was considered an important time to consider BMD evaluation because bone loss may be significant prior to menopause. However, because fracture risk is inherently low in women of this age without other risk factors, screening BMD testing is not appropriate. We discuss the risk factors that are strong indicators of fracture risk that may be increased during the menopause transition. The presence of these risk factors are appropriate indications for BMD testing with applicability of WHO diagnostic categorization. The issue of establishing a high threshold for BMD was investigated thoroughly and the current literature was reviewed. Despite the fact there is agreement that all BMD values greater than T-score -1.0 are not normal, it was felt that because of the paucity of sensitivity data and confounding factors such as high body mass index, an upper threshold could not be established or recommended at this time. This was felt to be an important area for further research.

Proceedings of the Eighth Annual Santa Fe Bone Symposium, August 3-4, 2007.

The Eighth Annual Santa Fe Bone Symposium convened August 3-4, 2007, in Santa Fe, New Mexico, USA, immediately preceded by the Research Symposium in Metabolic Bone Disease and Osteoporosis Update for Endocrine Fellows, and followed by the International Society for Clinical Densitometry (ISCD) Bone Densitometry Course. The symposium faculty consists of internationally recognized experts in osteoporosis and metabolic bone disease who presented state-of-the-art research data and late-breaking developments in the fields of osteoporosis, metabolic bone disease, and assessment of skeletal health. The presentations and numerous interactive discussions that followed focused on applying what is known from clinical trials, knowledge of bone pathophysiology, and the mechanisms of action of therapeutic interventions, to making real-world patient management decisions. Topics included an update on reimbursement issues for bone density testing in the United States, a report on the 2007 ISCD Pediatric and Adult Position Development Conferences, present and future therapeutic concepts, new paradigms for fracture risk assessment and intervention thresholds, evaluation for secondary causes of osteoporosis, nonvertebral fracture risk reduction-medical evidence and clinical practice, epidemiological insights into the prevention of osteoporotic fractures, osteonecrosis of the jaw facts and fictions, and osteomalacia. Presented here are short essays based on the key clinical presentations of the 2007 Santa Fe Bone Symposium.

New and emerging treatments for osteoporosis.

PURPOSE OF REVIEW: This review will focus on three new treatments for postmenopausal osteoporosis which have either been recently released (intravenous ibandronate), or have completed (zoledronic acid) or are currently in (denosumab) phase III trials. RECENT FINDINGS: A number of agents have demonstrated fracture risk reduction in randomized clinical trials, however, successful treatment of osteoporosis in the individual patient remains a challenge. Adherence to, and persistence with, all current osteoporosis medications are poor, being approximately 50% at 1 year for weekly bisphosphonates. Poor adherence to therapy makes it unlikely that the significant fracture reduction seen in clinical trials will be realized in clinical practice. SUMMARY: New therapies will not only have to demonstrate safety and efficacy, but also provide some advantage to patient persistence through either less frequent dosing schedules or elimination of gastrointestinal disturbances, the most common adverse effects encountered with bisphosphonates. This review will focus on three such agents that have either been recently released (intravenous ibandronate), or have completed (zoledronic acid) or are currently in (denosumab) phase III trials.

Recent developments in bisphosphonate therapy.

OBJECTIVE: To provide a review of current developments in bisphosphonates indicated for the treatment of several rheumatologic conditions, including postmenopausal and glucocorticoid-induced osteoporosis. METHODS: This review summarizes the pathology, diagnosis, and treatment of both postmenopausal and glucocorticoid-induced osteoporosis and examines the results of current clinical trials of the newest oral and intravenous formulations of nitrogen-containing bisphosphonates. We discuss important adverse events, including upper gastrointestinal symptoms and osteonecrosis of the jaw. Additionally, we explore methods that may improve patient adherence to bisphosphonate therapy, which is currently suboptimal. RESULTS: Clinical studies have shown that oral bisphosphonates are efficacious in increasing bone mineral density and reducing risk of fracture. Despite concerns of upper gastrointestinal irritation, most of the newer oral bisphosphonates display a safety profile similar to placebo. Many of the newest formulations offer patients a choice in both dosing frequency and method of administration (either oral or intravenous). CONCLUSIONS: Nitrogen-containing bisphosphonates are important therapeutic options for the prevention and treatment of osteoporosis.

Zoledronic acid for Paget's disease of bone.

Paget's disease of bone is a common skeletal disorder that often results in significant pain and disability. A number of bisphosphonates are currently available for treatment, however normalization of biochemical markers of bone turnover (the goal of treatment of Paget's disease) is rarely accomplished with currently available medications due to difficulty with administration, poor long-term adherence and possibly resistance to individual bisphosphonates. This review will focus on zoledronic acid, a potent intravenous bisphosphonate that appears to result in a higher percentage of patients with long-term normalization of markers of bone turnover than previously available drugs, thereby improving quality of life in patients with Paget's disease of bone.

The use of zoledronic acid for Paget's disease of bone.

Paget's disease of bone is a common skeletal disorder of the elderly that often results in significant morbidity and disability. Although there are a number of oral bisphosphonates currently available for treatment, normalization of biochemical markers of bone turnover with these agents is rarely accomplished due to difficulty with administration, adherence, and possibly resistance to individual bisphosphonates. This paper will focus on zoledronic acid, a potent and easily administered intravenous bisphosphonate that appears to result in a higher percentage of patients with normalization of markers of bone turnover and results in improvements in quality of life in patients with Paget's disease of bone.

Review of treatment modalities for postmenopausal osteoporosis.

This review summarizes and updates data presented at recent annual Southern Medical Association conferences on postmenopausal osteoporosis. As part of any osteoporosis treatment program, it is important to maintain adequate calcium and 25-hydroxyvitamin D levels either through diet or supplementation. Among the available pharmacologic therapies, the bisphosphonates alendronate and risedronate have demonstrated the most robust fracture risk reductions-approximately 40 to 50% reduction in vertebral fracture risk, 30 to 40% in nonvertebral fracture risk, and 40 to 60% in hip fracture risk. Ibandronate, a new bisphosphonate, has demonstrated efficacy in reducing vertebral fracture risk. Salmon calcitonin nasal spray and raloxifene demonstrated significant reductions in vertebral fracture risk in pivotal studies. Teriparatide significantly reduced vertebral and nonvertebral fracture risk. Drugs on the horizon include strontium ranelate, which has been shown to reduce vertebral and nonvertebral fracture risk, and zoledronic acid, an injectable bisphosphonate that increased bone density with once-yearly administration.

Osteoporosis and rate of bone loss among postmenopausal survivors of breast cancer.

BACKGROUND: Breast cancer diagnosis and treatment may put women at higher risk for osteoporosis in later life. METHODS: In a subgroup of participants in the Women's Health Initiative Observational Study, authors of the current study investigated differences in bone mineral density (BMD, measured by dual-energy x-ray absorptiometry) between breast cancer survivors (n = 209) and a noncancer reference group (n = 5759). RESULTS: In comparison to the reference group, breast cancer survivors had significantly lower total body BMD value (0.989 vs. 1.013 g/cm(2), P = 0.001) and total hip BMD value (0.823 vs. 0.845 g/cm(2), P = 0.02) at baseline after adjustment for age, race/ethnicity, years since menopause, and clinical center. These lower BMD levels were largely explained by lower usage of hormone therapy (HT) among survivors: after additional statistical adjustment for HT, hip BMD values were 0.834 versus 0.844 g/cm(2) (P = 0.26), and total body values were 1.005 versus 1.013 g/cm(2) (P = 0.33) for survivors and reference women, respectively. More than 77% of survivors with osteoporosis were undiagnosed by their healthcare providers, and this was similar to the undiagnosed rate in the reference group (85.7%). Longitudinally, breast cancer survivors in this study did not demonstrate an accelerated rate of bone loss compared with the reference population. CONCLUSIONS: Associated with lower HT usage, postmenopausal survivors of breast cancer were more likely to have low BMD in comparison to other women of the same age; and many of these survivors with osteoporosis were undiagnosed.